The present invention concerns benzisoxazoles and phenones having central xcex12-adrenoceptor antagonist activity. It further relates to their preparation, compositions comprising them and their use as a medicine.
Central xcex12-adrenoceptor antagonists are known to increase noradrenaline release by blocking presynaptic xcex12-receptors which exert an inhibiting control over the release of the neurotransmitter. By increasing the noradrenaline concentrations, xcex12-antagonists can be used clinically for the treatment or prophylaxis of depression, cognitive disturbances, Parkinson""s disease, diabetes mellitus, sexual dysfunction and impotence, elevated intraocular pressure, and diseases related to disturbed enterokinesia, since all these conditions are associated with a deficiency of noradrenaline in the central or peripheral nervous system.
WO98/45297, published on Oct. 15, 1998, 1,2,3,4-tetrahydro-benzofuro-[3,2-c]pyridine derivatives having central xcex12-adrenoceptor antagonist activity.
1-(4-fluorophenyl)-4-(1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)-1-butanone derivatives are disclosed in Kimura et al. [Arch. Int. Pharmacodyn. Ther. (1971), 190(1), 124-134], Nagai et al. [Chem. Parm. Bull. (1979), 27(8), 1922-1926], Harbert et al. [J. Med. Chem. (1980), 23(6), 635-643 and Mol. Pharmacol. (1980), 17(1), 38-42], Wong et al. [Can. Eur. J. Pharmacol. (1981), 73(2-3), 163-173], Ismaiel et al. [Med. Chem. Res. (1996), 6(3), 197-211], WO 95/07075, WO 94/10989, WO 94/08040, JP 47,029,395, DE 2,514,084, ZA 6,705,178, U.S. Pat. Nos. 3,382,250, 4,001,263, 4,224,329 and 5,508,306
4-(3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl)-1-(4-fluorophenyl)-1-butanone derivatives are disclosed in Aksanova et al. [Khim. Farm. Zh. (1975), 9(1), 7-9] as central nervous system blocking agents.
The compounds of the present invention are novel and have a specific and selective binding affinity for the different known subtypes of the (xcex12-adrenoceptors, i.e. the xcex12A, xcex12B and xcex12C-adrenoceptor. When compared to the closest art compounds, the present compounds unexpectedly show an improvement in dissociation between binding affinity for the xcex12A-adrenoceptor and the dopamine D2 receptor which is particularly useful when treating depression.
The present invention concerns the compounds of formula 
the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein:
Alk is C5-12alkanediyl;
n is 1 or 2;
p is 1 and q is 2; or
p is 2 and q is 1;
X is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94 or NR2;
each R1 is independently hydrogen, halogen, C1-6alkyl, nitro, hydroxy or C1-4alkyl-oxy;
R2 is hydrogen, C1-6alkyl, aryl or C1-6alkyl substituted with aryl;
aryl is phenyl or phenyl substituted with a halogen or C1-6alkyl;
D is a radical of formula 
xe2x80x83wherein
m is 1 or 2;
each R3 independently is hydrogen, C1-4alkyl, C1-4alkyloxy or halo.
As used in the foregoing definitions the term halogen is generic to fluoro, chloro, bromo and iodo. The term C1-4alkyl as a group or part of a group defines straight and branched saturated hydro-carbons, having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 1,1-dimethylethyl, 2-methyl-propyl and the like. The term C1-6alkyl is meant to include C1-4alkyl radicals and the higher homologues thereof having 5 or 6 carbon atoms such as, for example, pentyl, hexyl and the like. The term C6-12alkanediyl defines bivalent straight or branch chained alkanediyl radicals having from 5 to 12 carbon atoms such as, for example, 1,6-hexanediyl, 1,7-heptanediyl, 1,8-octanediyl, 1,9-nonanediyl, 1,10-decanediyl, 1,11-undecanediyl, 1,12-dodecanediyl and the like. The term C5-12alkanediyl is meant to include C6-12alkanediyl and the lower homologue having 5 carbon atoms such as, for example, 1,5-pentanediyl and the like.
The addition salts as mentioned herein are meant to comprise the therapeutically active addition salt forms which the compounds of formula (I) are able to form with appropriate acids, such as, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, xcfx81-toluenesulfonic, cyclamic, salicylic, xcfx81-aminosalicylic, pamoic and the like acids.
The pharmaceutically acceptable addition salts as mentioned hereinabove are also meant to comprise the therapeutically active non-toxic base, in particular, a metal or amine addition salt forms which the compounds of formula (I) are able to form. Said salts can conveniently be obtained by treating the compounds of formula (I) containing acidic hydrogen atoms with appropriate organic and inorganic bases such as, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely said salt forms can be converted by treatment with an appropriate base or acid into the free acid or base form.
The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) are able to form and said solvates are meant to be included within the scope of the present invention. Examples of such solvates are, e.g. the hydrates, alcoholates and the like.
The N-oxide forms of the compounds of formula (I) are meant to comprise those compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide.
The term stereochemically isomeric forms as used herein defines all the possible isomeric forms in which the compounds of formula (I) may occur. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure.
Some of the compounds of formula (I) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
Whenever used hereinafter, the term compounds of formula (I) is meant to include also the N-oxide forms, the pharmaceutically acceptable addition salts and all stereoisomeric forms.
As used hereinafter, when the position of the R1 substituent is referred to, the following numbering is used: 
An interesting group of compounds are those compounds of formula (I) wherein n is 1 and R1 is hydrogen, chloro, fluoro, methyl, methoxy or nitro, in particular R1 is hydrogen, chloro or methoxy.
In case R1 is other than hydrogen, then R1 is suitably connected to the tricyclic ring system in the 6 or 7 position.
Another interesting group of compounds are those compounds of formula (I) wherein Alk is 1,5-pentanediyl.
Still another interesting group of compounds are those compounds of formula (I) wherein D is a radical of formula (a) and R3 is fluoro, bromo, methoxy, methyl or hydrogen, in particular, fluoro.
Compounds of formula (I) wherein D is a radical of formula (b) are also of particular interest.
Particular compounds are those compounds of formula (I) wherein X is O, S or NH.
The compounds of formula (I) can generally be prepared by N-alkylating an intermediate of formula (II) with an alkylating reagent of formula (III) following the procedure described in EP-A-0,037,265, EP-A-0,070,053, EP-A-0,196,132 and in EP-A-0,378,255. In particular, the N-alkylation may be performed in a reaction-inert solvent such as, for example, methyl isobutyl keton, N,N-dimethylformamide or N,N-dimethylacetamide, in the presence of a base such as, for example, triethylamine, sodium carbonate or sodiumbicarbonate, and optionally in the presence of a catalyst such as, for example, potassium iodide. 
In intermediate (III), W1 represents an appropriate reactive leaving group such as, for example, halo, e.g. chloro, bromo or iodo; sulfonyloxy, e.g. methanesulfonyloxy, 4methylbenzenesulfonyloxy.
In this and the following reactions, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as extraction, crystallization, trituration and chromatography.
The compounds of formula (I) may be converted into each other following art-known functional group transformation reactions.
The compounds of formula (I) may also be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarbo-peroxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzene-carboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. tert-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
A number of intermediates and starting materials are commercially available or are known compounds which may be prepared according to art-known methodologies.
For example, some of the intermediates of formula (III) and their preparations are described in EP-A-0,037,265, EP-A-0,070,053, EP-A-0,196,132 and in EP-A-0,378,255.
Intermediates of formula (II) wherein X is O can be prepared analogous to the procedures described in Cattanach C. et al. (J. Chem. Soc (C), 1971, p53-60); Kartashova T. (Khim. Geterotsikl. Soedin., 1979 (9), p 1178-1180) and Zakusov. V. Et al. (Izobreteniya, 1992 (15), p 247). Intermediates of formula (II) wherein X is S can be prepared analogous to the procedure described in Capps et al (J. Am. Chem. Soc., 1953, p. 697) or U.S. Pat. No. 3,752,820.
A particular synthesis route for the preparation of intermediates of formula (II) wherein p is 1 and q is 2, said intermediates being represented by formula (II-1), is depicted in scheme 1. 
Step a can be performed analogous to the procedure described in Tetrahedron (1981), 37, p 979-982. Benzofurans resulting from step c have been used as intermediates in U.S. Pat. No. 4,210,655. The further reaction steps are analogous to the reaction procedures described in U.S. Pat. No. 3,752,820.
Alternatively, intermediates of formula (II-1) can be prepared using the reaction steps depicted in scheme 2. 
Step a can be performed analogous to the procedure described in Heterocycles (1994), 39(1), p. 371-380. Step b can be performed analogous to the procedure described in J. Med. Chem. (1986), 29(9), p. 1643-1650. Further reaction steps can be performed analogous to the ones described in J. Heterocycl. Chem. (1979), 16, p. 1321.
Intermediates of formula (II) wherein p is 2 and q is 1, said intermediates being represented by formula (II-2), can be prepared according to Synth. Comm., 1995, p3883-3900 and using methods known in the art. A general procedure is depicted in scheme 3. 
Intermediates of formula (II-2) wherein X is xe2x80x94Oxe2x80x94, said intermediates being represented by formula (II-2-a), can be prepared as described in Syn. Comm. (1995), p3883-3900 and J. Chem. Soc., 1965, p4939-4953 and using methods known in the art. A general procedure is depicted in scheme 4. 
Intermediates of formula (II-2) wherein X is xe2x80x94Sxe2x80x94, said intermediates being represented by formula (II-2-b), can be prepared according to J. Med. Chem., 1992, 35(7), p1176-1182 and using methods known in the art. A general procedure is depicted in scheme 5. 
Some of the compounds of formula (I) and some of the intermediates in the present invention contain at least one asymmetric carbon atom. Pure stereochemically isomeric forms of said compounds and said intermediates can be obtained by the application of art-known procedures. For example, diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastereomeric salts or compounds; then physically separating said mixtures of diastereomeric salts or compounds by, for example, selective crystallization or chromatographic techniques, e.g. liquid chromatography and the like methods; and finally converting said separated diastereomeric salts or compounds into the corresponding enantiomers.
Pure stereochemically isomeric forms of the compounds of formula (I) may also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that the intervening reactions occur stereospecifically. The pure and mixed stereochemically isomeric forms of the compounds of formula (I) are intended to be embraced within the scope of the present invention.
The compounds of formula (I), the N-oxides, the pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof, block the presynaptic xcex12-receptors on central noradrenergic neurons thus increasing the noradrenaline release. Blocking said receptors will suppress or relieve a variety of symptoms associated with a deficiency of noradrenaline in the central or peripheral nervous system. Therapeutic indications for using the present compounds are depression, cognitive disturbances, Parkinson""s disease, diabetes mellitus, sexual dysfunction and impotence and elevated intraocular pressure.
In particular, the present compounds show a larger dissociation between binding affinity for xcex12-receptors and that for dopamine receptors, especially between xcex12A-receptors and dopamine D2 receptors. This larger dissociation reduces the risk of extrapyramidal side effects (EPS) that might arise from dopamine receptor blockade and that should be avoided in the treatment of depression.
Blocking xcex12 receptors in the central nervous system has also been shown to enhance the release of serotonine which may add to the therapeutic action in depression (Maura et al., 1992, Naunyn-Schmiedeberg""s Arch. Pharmacol., 345: 410-416).
It has also been shown that blocking xcex12 receptors may induce an increase of extracellular DOPAC (3,4-dihydro-phenylacetic acid) which is a metabolite of dopamine and noradrenaline.
In view of the usefulness of the subject compounds in the treatment of diseases associated with a deficiency of noradrenaline in the central nervous system, in particular depression and Parkinson""s disease, the present invention provides a method of treating warm-blooded animals suffering from such diseases, in particular depression and Parkinson""s disease, said method comprising the systemic administration of an therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable addition salt thereof.
The present compounds are also potentially useful in the treatment of Alzheimer""s disease and dementia as it is known that xcex12-antagonists promote the release of acetylcholine (Tellez et al. 1997, J. Neurochem. 68:778-785).
In general it is contemplated that an effective therapeutic daily amount would be from about 0.01 mg/kg to about 4 mg/kg body weight.
The present invention thus also relates to compounds of formula (I) as defined
hereinabove for use as a medicine. Further, the present invention also relates to the use of a compound of formula (I) for the manufacture of a medicament for treating depression or Parkinson""s disease.
Ex vivo as well as in vitro receptor signal-transduction and receptor binding studies can be used to evaluate the xcex12 adrenoceptor antagonism of the present compounds. As indices of central a2-adrenoceptor blockade in vivo, the reversal of the loss of righting reflex observed in rats after intravenous injection of xylazine and inhibition of the tremors induced by reserpine in rats can be used.
The compounds of the present invention also have the ability to rapidly penetrate into the central nervous system.
For administration purposes, the subject compounds may be formulated into various pharmaceutical compositions comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound of formula (I). To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, in addition salt or in free acid or base form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable solutions containing compounds of formula (I) may be formulated in an oil for prolonged action. Appropriate oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soy bean oil, synthetic glycerol esters of long chain fatty acids and mixtures of these and other oils. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment. Addition salts of (I) due to their increased water solubility over the corresponding free base or free acid form, are obviously more suitable in the preparation of aqueous compositions.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.